RESUMEN
Objective: To evaluate the clinical safety and efficacy of toric intraocular lens (IOL) implantation for more than 5 years. Methods: This study was a prospective cohort study in which subjects were continuously observed over a two-year period (May 2014 to May 2016) in nine hospitals. The study randomly assigned subjects to two groups using a central dynamic randomization system: the study group, which received Proming® IQ toric IOL implants, and the control group, which received AcrySof® IQ toric IOL implants. The subjects completed a one-year follow-up, during which various measures were taken and evaluated, including visual acuity, IOL rotation, postoperative complications, intraocular pressure, and subjective evaluation (preoperatively and at 1 day, 6 months, 1 year, and 5 years post-surgery). The main statistical analysis methods include the Mann-Whitney U test, independent sample t-test, Wilcoxon signed rank test, paired sample t-test, chi-square test, and Fisher's exact test. Results: A total of 45 eyes (26 in the study group and 19 in the control group) completed the five-year continuous observation period. The mean age of the subjects was (72.07±10.67) years and the mean interval from surgery to the last visit was (5.39±0.47) years. After five years, there were no significant differences in uncorrected distance visual acuity (0.20±0.26 vs. 0.16±0.13, t=0.17,P=0.752), best corrected distance visual acuity[0.00(0.00, 0.20) vs. 0.05±0.10, U=188.00, P=0.880], uncorrected near visual acuity[0.50 (0.20, 0.60) vs. 0.42±0.20, t=0.35, P=0.857], and best corrected near visual acuity (0.13±0.16 vs. 0.17±0.23, U=161.00, P=0.884) between the two groups. However, all measures improved significantly from baseline levels in both groups (all P<0.05). Five years after surgery, no matter objective refraction [(-0.67±0.85) D vs. (-0.73±1.08)D] or subjective refraction[-0.50 (-1.00, 0.00)D vs. (0.69±0.87)D], the degree of cylindrical degree is significantly lower than preoperative corneal astigmatism [(1.27±0.49) D vs. (1.34±0.82) D, all P<0.001]. In addition, there were no significant differences in intraocular pressure, subjective evaluation of visual adverse symptoms, distance vision spectacle independence, or overall satisfaction evaluation between the two groups (all P>0.05). The IOL rotation was 3.0°(1.0°, 6.0°) in the study group and 4.0°(2.0°, 6.0°)in the control group (U=185.50,P=0.574), indicating no significant difference between the groups in terms of rotational stability. Five years after surgery, there were 7 cases of posterior capsular opacification in the study group and 4 cases in the control group. There were no cases of IOL glistening in the study group, but 5 cases (26.32%) were observed in the control group. Conclusions: The long-term effects of Proming® toric IOL implantation in correcting cataracts with regular corneal astigmatism are clear after five years, with few complications and stable results.
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Catarata , Implantación de Lentes Intraoculares , Anciano , Anciano de 80 o más Años , Humanos , Persona de Mediana Edad , Astigmatismo/cirugía , Opacificación Capsular/cirugía , Enfermedades de la Córnea/cirugía , Implantación de Lentes Intraoculares/efectos adversos , Implantación de Lentes Intraoculares/métodos , Lentes Intraoculares , Estudios Prospectivos , Refracción OcularRESUMEN
Objective: To evaluate the effectiveness and safety of Proming(®)Toric intraocular lens (IOL) in adults with cataract combined with corneal regular astigmatism. Methods: Multicentre, randomized, open and positive parallel controlled clinical study. A total of 121 patients (121 eyes) who had cataract combined with corneal regular astigmatism and met the inclusion criteria were enrolled in 9 hospitals from May 2014 to May 2016. There were 45 males and 76 females and the median age was 71 (42-88) years old. A total of 121 patients (121 eyes) were randomly assigned to the study group and the control group through the Central Randomization System. Sixty patients (60 eyes) of the study group were implanted with Proming(®)Toric IOL (Model: AT1BH-AT6BH) from Eyebright Medical Technology (Beijing) Co., Ltd., and 61 patients (61 eyes) of the control group were implanted with AcrySof (®)IQ Toric IOL (Model: SN6AT2-SN6AT7) from Alcon Laboratories, Inc. The visual acuity, IOL axial position, slit lamp examination, residual astigmatism and contrast sensitivity were recorded at 1 day, 1 week, 1 month, 3 months, 6 months and 1 year postoperatively. Statistical analysis was performed using χ(2) test, independent sample t test, Mann-Whitney U test, Friedman repeated measured ANOVA on ranks and non-parametric 2-factor variance analysis. Results: A total of 118 patients completed 6 months of follow-up, including 59 from the study group and 59 from the control group. The difference between the two groups in terms of the percentage of best corrected distance visual acuity (BCDVA) reaching 20/40 was 1.69% [100% (59/59) vs. 98.31% (58/59) ], and the lower limit of the 95% CI (-1.60%) was greater than -10.00%. A total of 90 patients were followed up for 1 year, including 43 patients from study group and 47 patients from control group. At 1 year after operation, the percentages of the BCDVA up to 20/40 were 97.67%(42/43) in the study group and 97.87% (46/47) in the control group, and there was no significant difference between the two groups (χ(2)=0.00, P=0.95);the percentages of the uncorrected distance visual acuity (UCDVA) up to 20/40 were 81.40%(35/43) in the study group and 82.98%(39/47) in the control group, and there was no significant difference between the two groups (χ(2)=0.04, P=0.84). At 1 year follow-up, the difference of contrast sensitivity at 18.0 c/d under the bright light, dark light, bright glare and dark glare between the two groups was not statistically significant (U=468.50, P=0.17;U=528.00, P=0.28;U=465.50, P=0.19;U=629.00, P=0.39);the difference of residual astigmatism between the two groups was not statistically significant (U=798.50, P=0.08);the difference of IOL rotation degree between the two groups was not statistically significant (U=869.00, P=0.25). There were no severe inflammatory responses nor other complications associated with IOL in both groups at each follow-up point. Conclusion: The visual quality, astigmatism correction effect, rotation stability and safety of Proming(®)Toric IOL for the treatment of cataract combined with corneal regular astigmatism is equivalent to AcrySof(®) IQ Toric IOL. (Chin J Ophthalmol, 2018, 54: 349-356).
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Astigmatismo , Catarata , Implantación de Lentes Intraoculares , Lentes Intraoculares , Facoemulsificación , Adulto , Anciano , Anciano de 80 o más Años , Astigmatismo/terapia , Beijing , Catarata/terapia , Femenino , Humanos , Masculino , Estudios Prospectivos , Refracción Ocular , Resultado del TratamientoRESUMEN
Chronic hypoxia induces polycythemia, pulmonary hypertension, right ventricular hypertrophy, and weight loss. Hypoxia-inducible factor 1 (HIF-1) activates transcription of genes encoding proteins that mediate adaptive responses to hypoxia, including erythropoietin, vascular endothelial growth factor, and glycolytic enzymes. Expression of the HIF-1alpha subunit increases exponentially as O2 concentration is decreased. Hif1a-/- mouse embryos with complete deficiency of HIF-1alpha due to homozygosity for a null allele at the Hif1a locus die at midgestation, with multiple cardiovascular malformations and mesenchymal cell death. Hif1a+/- heterozygotes develop normally and are indistinguishable from Hif1a+/+ wild-type littermates when maintained under normoxic conditions. In this study, the physiological responses of Hif1a+/- and Hif1a+/+ mice exposed to 10% O2 for one to six weeks were analyzed. Hif1a+/- mice demonstrated significantly delayed development of polycythemia, right ventricular hypertrophy, pulmonary hypertension, and pulmonary vascular remodeling and significantly greater weight loss compared with wild-type littermates. These results indicate that partial HIF-1alpha deficiency has significant effects on multiple systemic responses to chronic hypoxia.
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Proteínas de Unión al ADN/genética , Hipoxia/genética , Hipoxia/fisiopatología , Proteínas Nucleares/genética , Factores de Transcripción , Animales , Presión Sanguínea , Ventrículos Cardíacos/fisiopatología , Heterocigoto , Homocigoto , Factor 1 Inducible por Hipoxia , Subunidad alfa del Factor 1 Inducible por Hipoxia , RatonesRESUMEN
PURPOSE: Hypoxia inducible factor-1 (HIF-1) is a transcription factor composed of HIF-1alpha and HIF-1beta subunits. HIF-1 transactivates multiple genes whose products play key roles in oxygen homeostasis, including vascular endothelial growth factor (VEGF). This study was designed to determine whether HIF-1 levels are increased in ischemic retina and whether there is a correlation with increased expression of VEGF. METHODS: C57BL/6J mice were killed at time points that span retinal vascular development (PO to adult), or on postnatal day (P) 7 they were placed in a 75% oxygen environment for 5 days and then removed to room air and killed after 0, 2, or 6, or 24 hours and 5 or 14 days. Eyes were frozen, and retinas were isolated and used for immunoblot analysis, or eyes were sectioned for immunohisto chemical staining for HIF-1alpha or HIF-1beta, or for in situ hybridization for VEGF. RESULTS: Immunoblots of retinal lysates showed low levels of HIF-1alpha at PO that were markedly increased at P4, remained high throughout the period of retinal vascular development and then decreased to an intermediate level in adults. HIF-1beta levels were relatively constant at all time points. In mice with oxygen-induced ischemic retinopathy, HIF-1alpha levels were increased in the retina. The peak of increase occurred at 2 hours, and levels returned to baseline by 24 hours. Immunohistochemistry showed increased staining for HIF-1alpha throughout the hypoxic inner retina, but not in the normoxic outer retina. There was no modulation of HIF-1beta levels. There was constitutive expression of VEGF mRNA in the inner nuclear layer that was increased 6 hours after the onset of hypoxia and remained elevated for several days. CONCLUSIONS: There are increased levels of HIF-1alpha in ischemic retina that show temporal and spatial correlation with increased expression of VEGF. These findings are consistent with the hypothesis that HIF-1 plays a role in upregulation of VEGF in ischemic retina.
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Proteínas de Unión al ADN/metabolismo , Factores de Crecimiento Endotelial/metabolismo , Isquemia/metabolismo , Linfocinas/metabolismo , Proteínas Nucleares/metabolismo , Enfermedades de la Retina/metabolismo , Vasos Retinianos/metabolismo , Factores de Transcripción/metabolismo , Envejecimiento/metabolismo , Animales , Cartilla de ADN/química , Factor 1 Inducible por Hipoxia , Subunidad alfa del Factor 1 Inducible por Hipoxia , Immunoblotting , Técnicas para Inmunoenzimas , Hibridación in Situ , Ratones , Ratones Endogámicos C57BL , ARN Mensajero/metabolismo , Enfermedades de la Retina/patología , Vasos Retinianos/crecimiento & desarrollo , Vasos Retinianos/patología , Factor A de Crecimiento Endotelial Vascular , Factores de Crecimiento Endotelial VascularRESUMEN
PURPOSE: To study the safety and efficacy of posterior scleral reinforcement (PSR) combined with phakic intraocular lens (PIOLs) implantation for highly myopic amblyopia in children. METHODS: This study included eight highly myopic children (11 eyes) who failed in conventional therapy for amblyopia using various combination of spectacles, contact lenses, and intensive patching before enrollment into this study. They were treated sequentially with PSR and PIOL implantation, and were followed up for 3 years after surgery. Uncorrected visual acuity (UCVA) and best corrected visual acuity (BCVA) in LogMAR, spherical equivalent power (SE), and complications were evaluated. RESULTS: Before surgery, the mean UCVA was 1.59±0.33, BCVA, 0.74±0.37, SE, -17.57±5.56D, the axial length (AL), 30.09±2.18 mm. After PSR, BCVA improved one line in three patients, the rest were unchanged, and AL was unchanged among all cases. Six eyes of three patients were implanted with an iris-claw PIOL and five eyes of five patients were implanted with a posterior PIOL. After completion of treatment, the mean UCVA was 0.44±0.21, BCVA 0.38±0.24, SE -0.54±0.74 D, and AL 30.35±2.29 mm. No patient experienced complications. CONCLUSION: Combined PSR and PIOL implantation treatment for highly myopic amblyopia in children is safe and effective.
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Ambliopía/cirugía , Implantación de Lentes Intraoculares , Miopía/cirugía , Procedimientos Quirúrgicos Oftalmológicos , Lentes Intraoculares Fáquicas , Esclerótica/trasplante , Adolescente , Ambliopía/fisiopatología , Niño , Femenino , Estudios de Seguimiento , Humanos , Masculino , Miopía/fisiopatología , Colgajos Quirúrgicos , Técnicas de Sutura , Donantes de Tejidos , Agudeza Visual/fisiologíaAsunto(s)
Parasimpaticomiméticos/farmacología , Glándula Parótida/efectos de los fármacos , Receptores Colinérgicos/efectos de los fármacos , Animales , Atropina/farmacología , Corteza Cerebral/efectos de los fármacos , Cobayas , Intestino Delgado , Músculo Liso/efectos de los fármacos , Ratas , Escopolamina/farmacologíaRESUMEN
PURPOSE: To evaluate the position of iris-claw phakic intraocular lens (ICPIOL) in highly myopic eyes by Scheimpflug photography (SP) and ultrasound biomicroscopy (UBM). METHODS: Nine eyes of five patients aged 31+/-10 years with average spherical equivalent of -16.04+/-5.46 D (range -7.88 to - 22.88 D) were enrolled in this prospective study and implanted with Verisyse ICPIOLs (AMO). The anterior segment was evaluated by SP and UBM preoperatively and for at least 1 month postoperatively. The statistical significance may be questionable due to the limited number (nine) of eyes. RESULTS: By SP and UBM, the distance between corneal endothelium and lens (anterior chamber depth) preoperatively was 3.10+/-0.14 and 3.07+/-0.11 mm, respectively; between ICPIOL and corneal endothelium (pseudo-anterior chamber depth), 1.88+/-0.09 and 1.99+/-0.12 mm, respectively; between lens and posterior surface of ICPIOL (IL), 0.76+/-0.13 and 0.67+/-0.06 mm, respectively; between superior optic edge and iris (SOEI), 0.23+/-0.23 and 0.58+/-0.24 mm, respectively; between inferior optic edge and iris (IOEI), 0.07+/-0.13 and 0.41+/-0.22 mm, respectively; between ICPIOL haptics and the angle of anterior chamber (HA), 0.90+/-0.17 and 1.45+/-0.13 mm, respectively. ACD was well correlated between the two methods, but PACD, IL, OEI, HA were not. The postoperative measures, except IL, were significantly different between the two methods. CONCLUSION: The differences between measurements by SP and UBM reveal the ICPIOL's position variations with change of body position. Nevertheless, it seems adequate that space is maintained between ICPIOL and corneal endothelium, angle, and crystalline lens. The ICPIOL implanted in phakic eyes seems a safe alternative for treatment of high myopia.
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Implantación de Lentes Intraoculares/métodos , Miopía/cirugía , Lentes Intraoculares Fáquicas , Adulto , Cámara Anterior/patología , Técnicas de Diagnóstico Oftalmológico , Endotelio Corneal/patología , Femenino , Humanos , Iris/patología , Cristalino/patología , Masculino , Microscopía Acústica , Persona de Mediana Edad , Miopía/patología , Fotograbar , Periodo Posoperatorio , Postura , Estudios Prospectivos , Reproducibilidad de los ResultadosRESUMEN
Bao gong teng A (BGT-A), a cholinergic tropane, was first separated from Erycibe obtusifolia Benth in China in 1978. 6 beta-Acetoxy nortropane (6 beta-AN), a new tropane analogue of BGT-A, was synthesized in 1983, in our university. Tropanes are generally known as M-cholinoceptor blockers, but 6 beta-AN is a M-cholinoceptor agonist. The levorotatory 6 beta-AN is an active form that has been proved in biological and competitive binding test. The receptor binding experiment of 6 beta-AN were compared with those of M-receptor agonists (oxotremorine, carbachol, BGT-A and pilocarpine) and antagonists (pirenzepine, gallamine, atropine, scopolamine and anisodamine) on 4 different target tissues. The affinity order (pKi) of 6 beta-AN to 4 tissues (heart, cortex-hippocampus, ileal longitudinal muscle and iris) were 7.7, 6.8, 5.6 and 5.5, respectively. 6 beta-AN improved performances of mice in three-arm maze. Down-step tests suggested some potential nootropic effect. 6 beta-AN decreased the heart rate and cardiac contraction, increased the ileal longitudinal muscle contraction and pupil constriction. All above mentioned biological effects were antagonized by atropine. In receptor kinetics studies, we found marked discrepancy between pD2 and pKi. "The stronger the agonist, the larger the difference" suggest that different biological amplification systems are involved. Study on the receptor regulation showed surprisingly a specific subtype receptor regulation and 6 beta-AN gave a downward regulation on M2-R subtype only. Our data show that 6 beta-AN gallamine, oxotremorine and carbachol are M2-R subtype selective agents, while pirenzepine and pilocarpine are M1-R subtype selective agents.
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Nortropanos/farmacología , Receptores Muscarínicos/efectos de los fármacos , Animales , Regulación hacia Abajo , Cobayas , Aprendizaje/efectos de los fármacos , Masculino , Ratones , Contracción Muscular/efectos de los fármacos , Músculo Liso/efectos de los fármacos , Contracción Miocárdica/efectos de los fármacos , Conejos , Ratas , Ratas Endogámicas , EstereoisomerismoRESUMEN
Radioreceptor binding assays using [3H]quinuclidinyl benzilate and [3H]pirenzepine were performed on the pons and medulla oblongata (MeOb) of rat brain. The M1 cholinergic receptor (M1-R) was found to account for approximately 30-40% of the total muscarinic receptors (M-R) in the pons and MeOb, and the M2 accounted for about 60-70%. The receptor binding capacities of scopolamine and atropine were compared with those of pirenzepine (Pir) and AF-DX 116 on the 2 parts of the brain. The affinity values (pKi) suggest that the selectivity of scopolamine for M1-R is greater than for M2-R, and that of atropine for M2 is greater than for M1. In conscious rabbits, the respiratory frequency (FR), tidal volume (TV), and minute ventilation volume (MVV) were determined. Arterial blood samples were taken intermittently and analyzed for pO2, pCO2, and pH. When pilocarpine (a M1-R subtype selective agonist) was given, excitatory effects on respiration were seen through FR, TV, MVV, and the pO2, pCO2, and pH. When 6 beta-acetoxy nortropane (6 beta-AN, a novel M2-R subtype selective agonist) was given, the effects were inhibitory. These results were reversed after administration of Pir, scopolamine, AF-DX 116, and atropine. Thus, it shows that Pir and scopolamine inhibit respiration by blocking the M1-R subtype of the respiratory center, while the excitatory effects of AF-DX 116 and atropine are brought about by blocking the M2-R subtype of the respiratory center.
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Receptores Muscarínicos/clasificación , Respiración/efectos de los fármacos , Animales , Atropina/farmacología , Análisis de los Gases de la Sangre , Femenino , Masculino , Bulbo Raquídeo/metabolismo , Pilocarpina/farmacología , Pirenzepina/análogos & derivados , Pirenzepina/farmacología , Puente/metabolismo , Conejos , Ensayo de Unión Radioligante , Ratas , Ratas Endogámicas , Ratas Wistar , Receptores Muscarínicos/efectos de los fármacos , Receptores Muscarínicos/fisiología , Centro Respiratorio/metabolismo , Escopolamina/farmacología , Volumen de Ventilación Pulmonar/efectos de los fármacosRESUMEN
Vascular endothelial growth factor (VEGF) is a potent mediator of endothelial barrier dysfunction, and is upregulated during ischemia in many organs. Because ventilated pulmonary ischemia causes a marked increase in pulmonary vascular permeability, we hypothesized that VEGF would increase during ischemic lung injury. To test this hypothesis, we measured VEGF expression by Northern and Western blot analysis in isolated ferret lungs after 45 (n = 12) or 180 (n = 12) min of ventilated (95% or 0% O(2)) ischemia. Pulmonary vascular permeability, assessed by measurement of osmotic reflection coefficient for albumin (sigma(alb)), was evaluated in the same lungs, as was expression of the transcription factor, hypoxia-inducible factor (HIF)-1alpha. Distribution of VEGF as a function of ischemic time and oxygen tension was also evaluated by immunohistochemical staining in separate groups of lungs (n = 3). VEGF messenger RNA (mRNA) increased 3-fold by 180 min of ventilated ischemia, independent of oxygen tension. VEGF protein increased in parallel to mRNA. Immunohistochemical staining demonstrated the appearance of VEGF protein along alveolar septae after 180 min of hyperoxic ischemia, and after 45 or 180 min of hypoxic ischemia. sigma(alb) was not altered by 45 min of hyperoxic ischemia (0.69+/-0.09 versus 0.50+/-0.12, respectively), but decreased significantly after 180 min of hyperoxic ischemia and after 45 and 180 min of hypoxic ischemia (0.20+/-0.03, 0.26+/-0.08, and 0.23+/-0.03, respectively; P<0.05). HIF-1alpha mRNA increased during both hyperoxic and hypoxic ischemia, but HIF-1alpha protein increased only during hypoxic ischemia. These results implicate VEGF as a potential mediator of increased pulmonary vascular permeability in this model of acute lung injury.
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Factores de Crecimiento Endotelial/metabolismo , Isquemia/metabolismo , Linfocinas/metabolismo , Oxígeno/farmacología , Alveolos Pulmonares/irrigación sanguínea , Alveolos Pulmonares/metabolismo , Factores de Transcripción , Animales , Northern Blotting , Western Blotting , Proteínas de Unión al ADN/metabolismo , Factores de Crecimiento Endotelial/análisis , Factores de Crecimiento Endotelial/genética , Hurones , Expresión Génica/fisiología , Hipoxia/metabolismo , Factor 1 Inducible por Hipoxia , Subunidad alfa del Factor 1 Inducible por Hipoxia , Inmunohistoquímica , Linfocinas/análisis , Linfocinas/genética , Masculino , Proteínas Nucleares/metabolismo , Técnicas de Cultivo de Órganos , Oxígeno/análisis , ARN Mensajero/análisis , Factor A de Crecimiento Endotelial Vascular , Factores de Crecimiento Endotelial VascularRESUMEN
HIF-1 is a heterodimeric transcription factor, induced by hypoxia, that is composed of HIF-1alpha and HIF-1beta protein subunits. It binds to promoter/enhancer elements and stimulates the transcription of hypoxia-inducible target genes, including glucose transporter-1 and the glycolytic enzymes. Because HIF-1 activation might promote cell survival in hypoxic tissues, we studied the effect of permanent middle cerebral artery occlusion on the expression of HIF-1alpha, HIF-1beta and several HIF-1 target genes in adult rat brain. After focal ischaemia, mRNAs encoding HIF-1alpha, glucose transporter-1 and several glycolytic enzymes were up-regulated in the peri-infarct penumbra. This was observed by 7.5 h after the onset of ischaemia and increased further at 19 and 24 h. Regional cerebral blood flow was moderately decreased at 1 and 24 h after the ischaemia in areas of HIF-1 and HIF-1 target gene induction. Because hypoxia induces HIF-1 in other tissues, systemic hypoxia (6% O2 for 4.5 h) was also shown to increase HIF-1alpha protein expression in the adult rat brain. It is proposed that decreased blood flow to the penumbra decreases the supply of oxygen and that this induces HIF-1 and its target genes. This is the first study to show induction of HIF-1 after focal ischaemia in brain. Increased expression of HIF-1 target genes as a result of HIF-1 activation by hypoxia may contribute to tissue viability in the hypoxic/ischaemic penumbra by increasing glucose transport and glycolysis.
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Encéfalo/metabolismo , Proteínas de Unión al ADN/genética , Regulación de la Expresión Génica , Hipoxia-Isquemia Encefálica/fisiopatología , Proteínas Nucleares/genética , Animales , Circulación Cerebrovascular/fisiología , Proteínas de Unión al ADN/biosíntesis , Regulación de la Expresión Génica/fisiología , Secuencias Hélice-Asa-Hélice , Factor 1 Inducible por Hipoxia , Subunidad alfa del Factor 1 Inducible por Hipoxia , Hipoxia-Isquemia Encefálica/etiología , Hibridación in Situ , Infarto de la Arteria Cerebral Media/complicaciones , Infarto de la Arteria Cerebral Media/fisiopatología , Masculino , Proteínas Nucleares/biosíntesis , ARN Mensajero/metabolismo , Ratas , Ratas Sprague-Dawley , Factores de Transcripción/biosíntesis , Factores de Transcripción/genética , Activación Transcripcional , Regulación hacia ArribaRESUMEN
OBJECTIVE: Our purpose was to determine whether the increase in fetal cardiac mass and cardiac output in chronic anemia is accompanied by changes in capillary density or size or changes in levels of vascular endothelial growth factor and hypoxia-inducible factor 1, a basic helix-loop-helix transcription factor that has previously been shown to activate vascular endothelial growth factor gene transcription when cultured cells are subjected to hypoxia. STUDY DESIGN: Anemia was induced in near-term ovine fetuses by daily isovolemic hemorrhage. In five fetuses the heart was arrested in diastole, isolated, and fixed at physiologic pressures with adenosine-paraformaldehyde, and morphometric measurements of capillaries were made. In six fetuses cardiac expression of vascular endothelial growth factor and hypoxia-inducible factor 1 protein was detected by Western analysis and vascular endothelial growth factor messenger ribonucleic acid by Northern blot analysis. Eleven age-matched fetuses served as controls. RESULTS: The anemic fetuses compared with controls had a lower hematocrit (14.8% +/- 0.7% vs 35.3% +/- 1.5%) and a greater heart-to-body weight ratio (10.5 +/- 1.1 vs 7.7 +/- 0.5 gm/kg). The minimal capillary diameter was increased and the intercapillary distance was decreased in both right and left ventricles of anemic fetuses compared with controls. Vascular endothelial growth factor protein was increased 4.5-fold, vascular endothelial growth factor messenger ribonucleic acid 3.2-fold, and hypoxia-inducible factor 1alpha protein 3.8-fold in ventricular tissue from anemic fetuses. CONCLUSIONS: In chronic fetal anemia cardiac hypertrophy is accompanied by anatomic changes in myocardial capillary morphometry along with induction of hypoxia-inducible factor 1 and vascular endothelial growth factor. These results provide evidence for a pathway by which anemia-hypoxia may stimulate myocardial vascularization.
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Anemia/fisiopatología , Cardiomegalia/fisiopatología , Circulación Coronaria/fisiología , Proteínas de Unión al ADN/metabolismo , Factores de Crecimiento Endotelial/metabolismo , Enfermedades Fetales/fisiopatología , Linfocinas/metabolismo , Miocardio/metabolismo , Proteínas Nucleares/metabolismo , Factores de Transcripción/metabolismo , Anemia/metabolismo , Anemia/patología , Animales , Capilares/patología , Gasto Cardíaco/fisiología , Cardiomegalia/metabolismo , Cardiomegalia/patología , Células Cultivadas , Enfermedad Crónica , Femenino , Enfermedades Fetales/metabolismo , Enfermedades Fetales/patología , Secuencias Hélice-Asa-Hélice , Humanos , Factor 1 Inducible por Hipoxia , Subunidad alfa del Factor 1 Inducible por Hipoxia , Ovinos , Factor A de Crecimiento Endotelial Vascular , Factores de Crecimiento Endotelial VascularRESUMEN
Hypoxia-inducible factor-1 (HIF-1) is a heterodimer composed of HIF-1alpha and HIF-1beta protein subunits. This transcription factor is essential for the activation of hypoxia-inducible genes like erythropoietin, some glucose transporters, the glycolytic enzymes, and vascular endothelial growth factor. Because HIF-1 activation may promote cell survival in hypoxic tissues, we studied the effect of hypoxic preconditioning on HIF-1 expression in neonatal rat brain. Hypoxic preconditioning (8% O2 for 3 hours), a treatment known to protect the newborn rat brain against hypoxic-ischemic injury, markedly increased HIF-1alpha and HIF-1beta expression. To support the role of HIF-1 in protective preconditioning, we also studied the effect of two other known HIF-1 inducers, cobalt chloride (CoCl2) and desferrioxamine (DFX), on HIF-1 expression and neuroprotection in newborn brain. HIF-1alpha and HIF-1beta protein levels were markedly increased after intraperitoneal injection of CoCl2 (60 mg/kg) and moderately increased after intraperitoneal injection of DFX (200 mg/kg) 1 to 3 hours after the injections. Preconditioning with CoCl2 or DFX 24 hours before hypoxia-ischemia afforded 75 and 56% brain protection, respectively, compared with that in vehicle-injected littermate controls. Thus, HIF-1 activation could contribute to protective brain preconditioning, which could be used in high-risk deliveries and other clinical situations.
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Proteínas de Unión al ADN/metabolismo , Hipoxia-Isquemia Encefálica/metabolismo , Proteínas Nucleares/metabolismo , Factores de Transcripción , Animales , Western Blotting , Femenino , Regulación de la Expresión Génica , Factor 1 Inducible por Hipoxia , Subunidad alfa del Factor 1 Inducible por Hipoxia , Inmunohistoquímica , Masculino , Ratas , Ratas Sprague-DawleyRESUMEN
Hypoxia-inducible factor (HIF)-1 is a basic helix-loop-helix transcription factor that transactivates genes encoding proteins that participate in homeostatic responses to hypoxia. Several of these downstream gene products, such as erythropoietin, vascular endothelial growth factor, heme oxygenase-1, and inducible nitric oxide synthase, may contribute to the pathogenesis of pulmonary hypertension. Previous studies demonstrated increased HIF-1 mRNA levels in rats and mice subjected to hypoxia. In this study, we have demonstrated spatial, temporal, and O2-dependent expression of HIF-1 protein. Immunoblot analysis revealed hypoxic induction of HIF-1 in all cultured pulmonary cell types assayed, including those derived from pulmonary arterial endothelium and smooth muscle, bronchial epithelium, alveolar macrophages, alveolar epithelium, and microvascular endothelium. In contrast to all other cell types, pulmonary arterial smooth muscle cells expressed HIF-1 under nonhypoxic conditions. Immunohistochemistry and immunoblot analysis of ferret lungs demonstrated pulmonary expression of HIF-1 in vivo. HIF-1 protein expression was induced maximally when lungs were ventilated with 0 or 1% O2 for 4 h. On reoxygenation, HIF-1 was rapidly degraded, with a half-life of <1 min. These findings demonstrate that HIF-1 expression is tightly coupled to O2 concentration in vivo and are consistent with the involvement of HIF-1 in the physiological and pathophysiological responses to hypoxia in the lung.
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Proteínas de Unión al ADN/genética , Endotelio Vascular/metabolismo , Regulación de la Expresión Génica , Pulmón/metabolismo , Proteínas Nucleares/genética , Arteria Pulmonar/metabolismo , Animales , Aorta , Bronquios/metabolismo , Células Cultivadas , Proteínas de Unión al ADN/biosíntesis , Proteínas de Unión al ADN/metabolismo , Endotelio Vascular/citología , Células Epiteliales/metabolismo , Secuencias Hélice-Asa-Hélice , Hipoxia , Factor 1 Inducible por Hipoxia , Subunidad alfa del Factor 1 Inducible por Hipoxia , Pulmón/citología , Macrófagos Alveolares/metabolismo , Ratones , Microcirculación , Músculo Liso Vascular/citología , Músculo Liso Vascular/metabolismo , Proteínas Nucleares/biosíntesis , Proteínas Nucleares/metabolismo , Alveolos Pulmonares/metabolismo , Arteria Pulmonar/citología , Ratas , Ovinos , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Transcripción GenéticaRESUMEN
In a previous study we have shown that perioperative monitoring for silent myocardial ischemia can noninvasively identify those patients undergoing peripheral vascular surgery who are at significantly increased risk for perioperative myocardial infarction. In the present study a group of 385 patients undergoing peripheral vascular surgery was studied long-term as well as short-term to determine whether perioperative monitoring for silent ischemia can identify those patients who are at significantly increased risk of late cardiac death or late cardiac complications as well as those patients at increased risk of perioperative myocardial infarction. All patients were monitored before, during, and after operation and were divided into two groups on the basis of results of monitoring: patients whose total duration of silent ischemia as a percentage of the total duration of perioperative monitoring was 1% or greater (group I, n = 120) and those for whom this value was less than 1% (group II, n = 265). Among patients in group I 13.3% (16 of 120) suffered a perioperative myocardial infarction in contrast to only 1.1% (3 of 265) patients in group II (p less than 0.001). Multivariate logistic regression analysis of preoperative and perioperative characteristics showed that the presence of a total perioperative percent time ischemic 1% or greater and age were the only significant predictors of perioperative myocardial infarction.(ABSTRACT TRUNCATED AT 250 WORDS)
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Enfermedad Coronaria/diagnóstico , Enfermedades Vasculares Periféricas/cirugía , Anciano , Distribución de Chi-Cuadrado , Enfermedad Coronaria/complicaciones , Enfermedad Coronaria/mortalidad , Electrocardiografía , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Monitoreo Intraoperatorio , Monitoreo Fisiológico , Enfermedades Vasculares Periféricas/complicaciones , Cuidados Posoperatorios , Complicaciones Posoperatorias/diagnóstico , Complicaciones Posoperatorias/etiología , Complicaciones Posoperatorias/mortalidad , Valor Predictivo de las Pruebas , Cuidados Preoperatorios , Análisis de Regresión , Análisis de SupervivenciaRESUMEN
Hypoxia is an essential developmental and physiological stimulus that plays a key role in the pathophysiology of cancer, heart attack, stroke, and other major causes of mortality. Hypoxia-inducible factor 1 (HIF-1) is the only known mammalian transcription factor expressed uniquely in response to physiologically relevant levels of hypoxia. We now report that in Hif1a-/- embryonic stem cells that did not express the O2-regulated HIF-1alpha subunit, levels of mRNAs encoding glucose transporters and glycolytic enzymes were reduced, and cellular proliferation was impaired. Vascular endothelial growth factor mRNA expression was also markedly decreased in hypoxic Hif1a-/- embryonic stem cells and cystic embryoid bodies. Complete deficiency of HIF-1alpha resulted in developmental arrest and lethality by E11 of Hif1a-/- embryos that manifested neural tube defects, cardiovascular malformations, and marked cell death within the cephalic mesenchyme. In Hif1a+/+ embryos, HIF-1alpha expression increased between E8.5 and E9.5, coincident with the onset of developmental defects and cell death in Hif1a-/- embryos. These results demonstrate that HIF-1alpha is a master regulator of cellular and developmental O2 homeostasis.